Novak Djokovic will begin his US Open defence against Jerzy Janowicz, while Serena Williams' quest for a record 23rd Open Era grand slam starts against Ekaterina Makarova.
After exiting Wimbledon to Sam Querrey in the third round this year and losing to Juan Martin del Potro in the first round at Rio 2016, Djokovic will be aiming to win his 13th major in New York.
The Serbian will be confident of a strong start at the US Open, with world number 228 Janowicz having only returned from a six-month lay-off in July.
Djokovic is joined in the top half of the draw by Rafael Nadal - who kicks off his campaign against Denis Istomin - and Milos Raonic, the Spaniard and Canadian potential semi-final opponents.
Double Olympic champion Andy Murray, who has been struggling with a shoulder injury and lost the Western and Southern Open final to Marin Cilic, will face Lukas Rosol in his first match.
The world number two could face Kei Nishikori - who starts against Benjamin Becker - in the quarter-finals and Stan Wawrinka or Del Potro in the semis.
In the women's draw, Williams will be looking to surpass her run to the final four in 2015 against a familiar foe.
The world number one overcame Makarova en route to the 2012 and 2014 titles in Flushing Meadows and will need to do so again if she is to be victorious this year.
However, things could get tricky with a potential third-round match against Ana Ivanovic, quarter-final versus Simona Halep and a possible semi with sister Venus or Agnieszka Radwanska.
Angelique Kerber will be looking to displace Williams at the top of the rankings at the US Open, and Polona Hercog will be her first opponent.
French Open champion Garbine Muguruza will face a qualifier in the first round, and a match with Olympic champion Monica Puig could occur in round three.